Natural killer (NK) cells are critically important for tumor surveillance and regulating tumor metastasis. Chemokines and their receptors regulate organ-specific leukocyte trafficking and inflammation, and the chemokine fractalkine (FKN, CX3CL1), with its receptor (CX3CR1), is one of the most effective chemoattractants for NK cells. In addition to the chemotactic properties attributed to chemokines, FKN and CX3CR1 have remarkable cell adhesion properties that may contribute to cell migration and function. In vitro, these cell adhesion properties promote conjugate formation between NK cells and their targets to enhance killing of FKN-expressing targets like epithelial cells. Our preliminary studies, using the B16 metastatic melanoma model that is dependent on NK cell activity for melanoma clearance, indicate that CX3CR1-deficient animals are defective in controlling the growth of and clearing melanoma lung metastases. The mechanisms by which CX3CR1 regulates the anti-tumor effects of NK cells remain to be determined. The hypothesis we are testing is that FKN and CX3CR1 regulate the host immune response to epithelial cancers such as metastatic melanoma by affecting NK cell trafficking and function. Our aims are to: (1) determine whether the observed defects in the ability of CX3CR1-deficient mice to clear metastatic melanoma are due to defects in NK cell development, trafficking, cytokine production or cytolytic activity, (2) to define the contributions of CX3CR1 signaling and cell adhesion to NK cell trafficking and function, and (3) to determine whether CX3CR1 may play a role in regulating anti-tumor responses in man by examining the differential effects of naturally occurring human CX3CR1 variants on NK cell function and anti-tumor responses.